Electric utility acid fuel cell stack technology advancement

The principal effort under this program was directed at the fuel cell stack technology required to accomplish the initial feasibility demonstrations of increased cell stack operating pressures and temperatures, increased cell active area, incorporation of the ribbed substrate cell configuration at the bove conditions, and the introduction of higher performance electrocatalysts. The program results were successful with the primary accomplishments being: (1) fabrication of 10 sq ft ribbed substrate, cell components including higher performing electrocatalysts; (2) assembly of a 10 sq ft, 30-cell short stack; and (3) initial test of this stack at 120 psia and 405 F. These accomplishments demonstrate the feasibility of fabricating and handling large area cells using materials and processes that are oriented to low cost manufacture. An additional accomplishment under the program was the testing of two 3.7 sq ft short stacks at 12 psia/405 F to 5400 and 4500 hours respectively. These tests demonstrate the durability of the components and the cell stack configuration to a nominal 5000 hours at the higher pressure and temperature condition planned for the next electric utility power plant

Impairment of early fracture healing by skeletal muscle trauma is restored by FK506

BACKGROUND: Heightened local inflammation due to muscle trauma or disease is associated with impaired bone regeneration. METHODS: We hypothesized that FK506, an FDA approved immunomodulatory compound with neurotrophic and osteogenic effects, will rescue the early phase of fracture healing which is impaired by concomitant muscle trauma in male (~4 months old) Lewis rats. FK506 (1 mg/kg; i.p.) or saline was administered systemically for 14 days after an endogenously healing tibia osteotomy was created and fixed with an intermedullary pin, and the overlying tibialis anterior (TA) muscle was either left uninjured or incurred volumetric muscle loss injury (6 mm full thickness biopsy from middle third of the muscle). RESULTS: The salient observations of this study were that 1) concomitant TA muscle trauma impaired recovery of tibia mechanical properties 28 days post-injury, 2) FK506 administration rescued the recovery of tibia mechanical properties in the presence of concomitant TA muscle trauma but did not augment mechanical recovery of an isolated osteotomy (no muscle trauma), 3) T lymphocytes and macrophage presence within the traumatized musculature were heightened by trauma and attenuated by FK506 3 days post-injury, and 4) T lymphocyte but not macrophage presence within the fracture callus were attenuated by FK506 at 14 days post-injury. FK506 did not improve TA muscle isometric torque production CONCLUSION: Collectively, these findings support the administration of FK506 to ameliorate healing of fractures with severe muscle trauma comorbidity. The results suggest one potential mechanism of action is a reduction in local T lymphocytes within the injured musculoskeletal tissue, though other mechanisms to include direct osteogenic effects of FK506 require further investigation

Decellularised skeletal muscles allow functional muscle regeneration by promoting host cell migration

Pathological conditions affecting skeletal muscle function may lead to irreversible volumetric muscle loss (VML). Therapeutic approaches involving acellular matrices represent an emerging and promising strategy to promote regeneration of skeletal muscle following injury. Here we investigated the ability of three different decellularised skeletal muscle scaffolds to support muscle regeneration in a xenogeneic immune-competent model of VML, in which the EDL muscle was surgically resected. All implanted acellular matrices, used to replace the resected muscles, were able to generate functional artificial muscles by promoting host myogenic cell migration and differentiation, as well as nervous fibres, vascular networks, and satellite cell (SC) homing. However, acellular tissue mainly composed of extracellular matrix (ECM) allowed better myofibre three-dimensional (3D) organization and the restoration of SC pool, when compared to scaffolds which also preserved muscular cytoskeletal structures. Finally, we showed that fibroblasts are indispensable to promote efficient migration and myogenesis by muscle stem cells across the scaffolds in vitro. This data strongly support the use of xenogeneic acellular muscles as device to treat VML conditions in absence of donor cell implementation, as well as in vitro model for studying cell interplay during myogenesis

Early initiation of electrical stimulation paired with range of motion after a volumetric muscle loss injury does not benefit muscle function

Abstract Volumetric muscle loss (VML) injury occurs when a substantial volume of muscle is lost by surgical removal or trauma, resulting in an irrecoverable deficit in muscle function. Recently, it was suggested that VML impacts whole‐body and muscle‐specific metabolism, which might contribute to the inability of the muscle to respond to treatments such as physical rehabilitation. The aim of this work was to understand the complex relationship between physical activity and the response to rehabilitation after VML in an animal model, evaluating the rehabilitation response by measurement of muscle function and whole‐body metabolism. Adult male mice (n = 24) underwent a multi‐muscle, full‐thickness VML injury to the gastrocnemius, soleus and plantaris muscles and were randomized into one of three groups: (1) untreated; (2) rehabilitation (i.e., combined electrical stimulation and range of motion, twice per week, beginning 72 h post‐injury, for ∼8 weeks); or (3) rehabilitation and restriction of physical activity. There was a lack of positive adaption associated with electrical stimulation and range of motion intervention alone; however, maximal isometric torque of the posterior muscle group was greater in mice receiving treatment with activity restriction (P = 0.008). Physical activity and whole‐body metabolism were measured ∼6 weeks post‐injury; metabolic rate decreased (P = 0.001) and respiratory exchange ratio increased (P = 0.022) with activity restriction. Therefore, restricting physical activity might enhance an intervention delivered to the injured muscle group but impair whole‐body metabolism. It is possible that restricting activity is important initially post‐injury to protect the muscle from excess demand. A gradual increase in activity throughout the course of treatment might optimize muscle function and whole‐body metabolism

Resistance wheel running improves contractile strength, but not metabolic capacity, in a murine model of volumetric muscle loss injury

Abstract The primary objective of this study was to determine if low‐ or high‐resistance voluntary wheel running leads to functional improvements in muscle strength (i.e., isometric and isokinetic torque) and metabolic function (i.e., permeabilized fibre bundle mitochondrial respiration) after a volumetric muscle loss (VML) injury. C57BL/6J mice were randomized into one of four experimental groups at age 12 weeks: uninjured control, VML untreated (VML), low‐resistance wheel running (VML‐LR) and high‐resistance wheel running (VML‐HR). All mice, excluding the uninjured, were subject to a unilateral VML injury to the plantar flexor muscles and wheel running began 3 days post‐VML. At 8 weeks post‐VML, peak isometric torque was greater in uninjured compared to all VML‐injured groups, but both VML‐LR and VML‐HR had greater (∼32%) peak isometric torque compared to VML. All VML‐injured groups had less isokinetic torque compared to uninjured, and there was no statistical difference among VML, VML‐LR and VML‐HR. No differences in cumulative running distance were observed between VML‐LR and VML‐HR groups. Because adaptations in VML‐HR peak isometric torque were attributed to greater gastrocnemius muscle mass, atrophy‐ and hypertrophy‐related protein content and post‐translational modifications were explored via immunoblot; however, results were inconclusive. Permeabilized fibre bundle mitochondrial oxygen consumption was 22% greater in uninjured compared to VML, but there was no statistical difference among VML, VML‐LR and VML‐HR. Furthermore, neither wheel running group demonstrated a change in the relative protein content of the mitochondrial biogenesis transcription factor, peroxisome proliferator‐activated receptor γ coactivator 1‐α (PGC‐1α). These results indicate that resistance wheel running alone only has modest benefits in the VML‐injured muscle

Exploring skeletal muscle tolerance and whole‐body metabolic effects of FDA‐approved drugs in a volumetric muscle loss model

Abstract Volumetric muscle loss (VML) is associated with persistent functional impairment due to a lack of de novo muscle regeneration. As mechanisms driving the lack of regeneration continue to be established, adjunctive pharmaceuticals to address the pathophysiology of the remaining muscle may offer partial remediation. Studies were designed to evaluate the tolerance and efficacy of two FDA‐approved pharmaceutical modalities to address the pathophysiology of the remaining muscle tissue after VML injury: (1) nintedanib (an anti‐fibrotic) and (2) combined formoterol and leucine (myogenic promoters). Tolerance was first established by testing low‐ and high‐dosage effects on uninjured skeletal muscle mass and myofiber cross‐sectional area in adult male C57BL/6J mice. Next, tolerated doses of the two pharmaceutical modalities were tested in VML‐injured adult male C57BL/6J mice after an 8‐week treatment period for their ability to modulate muscle strength and whole‐body metabolism. The most salient findings indicate that formoterol plus leucine mitigated the loss in muscle mass, myofiber number, whole‐body lipid oxidation, and muscle strength, and resulted in a higher whole‐body metabolic rate (p ≤ 0.016); nintedanib did not exacerbate or correct aspects of the muscle pathophysiology after VML. This supports ongoing optimization efforts, including scale‐up evaluations of formoterol treatment in large animal models of VML

Estradiol's beneficial effect on murine muscle function is independent of muscle activity

Estradiol (E2) deficiency decreases muscle strength and wheel running in female mice. It is not known if the muscle weakness results directly from the loss of E2 or indirectly from mice becoming relatively inactive with presumably diminished muscle activity. The first aim of this study was to determine if cage activities of ovariectomized mice with and without E2 treatment differ. Ovariectomized mice were 19–46% less active than E2-replaced mice in terms of ambulation, jumping, and time spent being active (P ≤ 0.033). After E2-deficient mice were found to have low cage activities, the second aim was to determine if E2 is beneficial to muscle contractility, independent of physical activities by the mouse or its hindlimb muscles. Adult, female mice were ovariectomized or sham-operated and randomized to receive E2 or placebo and then subjected to conditions that should maintain physical and muscle activity at a constant low level. After 2 wk of hindlimb suspension or unilateral tibial nerve transection, muscle contractile function was assessed. Soleus muscles of hindlimb-suspended ovariectomized mice generated 31% lower normalized (relative to muscle contractile protein content) maximal isometric force than suspended mice with intact ovaries (P ≤ 0.049). Irrespective of whether the soleus muscle was innervated, muscles from ovariectomized mice generated ∼20% lower absolute and normalized maximal isometric forces, as well as power, than E2-replaced mice (P ≤ 0.004). In conclusion, E2 affects muscle force generation, even when muscle activity is equalized